The proposed study will use dynamic molecular imaging to examine a novel hypothesis concerning nature of dysregulated dopamine neurotransmission in Tourette's syndrome (TS). It is known for several years that the dopamine system is dysregulated in TS, but the nature of dysregulation remains unclear because of contradictory evidence. Thus, symptomatic relief following administration of dopamine antagonists suggests hyperactivity of the dopamine system but the hyperactivity is not consistently supported by the data on receptor density, precursor and transporter uptake. Some of these data even suggest hypoactive dopamine. To reconcile contradictory data we hypothesize that the tonic pool of dopamine is attenuated in TS. It leads to compensatory enhancement of the phasic release. Increased phasic release is known to impair processing of the central inhibitory system, which in turn impairs the ability to inhibit unwanted response in TS patients. Consistent with this hypothesis, studies that have directly or indirectly measured the tonic pool have found reduced dopamine activity while those that have studied the phasic release have reported increased activity in TS. In the proposed study the validity of hypothesis will be examined by detecting, mapping and measuring the tonic and phasic release of dopamine in TS patients and matched healthy control volunteers using a recently developed dynamic molecular imaging technique. The tonic pool in the striatal and extrastriatal areas will be estimated by estimating the binding potentials (BP) of dopamine receptor ligands 11C-raclopride and 18F-fallypride respectively at rest. Comparison of the data acquired in the two groups will indicate whether the tonic pool is reduced in TS. For measurement of the phasic release, changes in the rate of ligand displacement (from receptor sites) and the ligand BP will be estimated during performance of a task that requires inhibition of an unwanted response (Eriksen's flanker task). During the task performance concentration of previously administered dopamine receptor ligand (11C-raclopride or 18F-fallypride) will be dynamically measured using a positron emission tomography (PET) camera. This measurement will be applied to newly developed receptor kinetic models to estimate values of the receptor kinetic parameters before and after task initiation. These measurements will help us detect, map and measure dopamine released during task performance. Comparison of the data acquired in TS patients and healthy control volunteers will indicate whether the phasic release is enhanced during response inhibition in TS. The study will advance our understanding of the nature of dysregulated dopamine neurotransmission in TS and demonstrate that the dynamic molecular imaging can be used to study dysregulated dopamine neurotransmission in neuropsychiatric conditions. Additionally, data acquired in the proposed experiments can be used to develop novel therapeutic strategies and targets for treatment and prevention of cognitive deficits in TS. PUBLIC HEALTH RELEVANCE: The proposed study will examine an important hypothesis concerning pathophysiology of Tourette syndrome, which is a disabling condition. The results will allow better understanding of neurocognitive deficits and could lead to development of novel therapeutic strategies and targets for treatment and prevention of cognitive deficits in Tourette's patients.